Monoclonal antibodies reactive with carcinoma-associated antigens are known [see, e.g., L. D. Papsidero, "Recent Progress in the Immunological Monitoring of Carcinomas Using Monoclonal Antibodies, Semin. Surg. Oncol., 1 (No. 4), pp. 171-81 (1985); J. Schlom et al., "Potential of Human Carcinomas", Important Adv. Oncol., 1985, pp. 170-192; W. H. Allum et al., "Monoclonal Antibodies in the Diagnosis and Treatment of Malignant Conditions", Surg. Ann., 18, pp. 41-64 (1986); and A. N. Houghton et al., "Monoclonal Antibodies: Potential Applications to the Treatment of Cancer", Semin. Oncol., 13 (No. 2), pp. 165-179 (1986)].
These known monoclonal antibodies are principally reactive with specific types of human carcinomas derived from specific organs of the body, e.g., lung, breast, ovarian, colon or other gastrointestinal carcinomas, and can bind to carcinoma-associated antigens that are either glycoprotein or glycolipid in nature [see, e.g., L. M. Fink et al., "Monoclonal Antibodies as Diagnostic Reagents for the Identification and Characterization of Human Tumor Antigens", Prog. Clin. Pathol., 9, pp. 121-133 (1984)]. For example, monoclonal antibodies that bind to glycoprotein antigens on specific types of carcinomas include those described in U.S. Pat. No. 4,737,579 (monoclonal antibodies to non-small cell lung carcinomas), U.S. Pat. No. 4,753,894 (monoclonal antibodies to human breast cancer), U.S. Pat. No. 4,579,827 (monoclonal antibodies to human gastrointestinal cancer), and U.S. Pat. No. 4,713,352 (monoclonal antibodies to human renal carcinoma) . Monoclonal antibody B72.3, however, appears to recognize a tumor-associated oncofetal glycoprotein antigen of greater than 1,000 kd molecular weight that is selectively expressed on a number of different carcinomas. Thus, B72.3 has been shown to react with 84% of breast carcinomas, 94% of colon carcinomas, 100% of ovarian carcinomas, and 96% of non-small-cell lung carcinomas [see W. W. Johnston, "Applications of Monoclonal Antibodies in Clinical Cytology as Exemplified by Studies with Monoclonal Antibody B72.3", Acta Cytol., 1 (No. 5), pp. 537-556 (1987), and U.S. Pat. No. 4,612,282, issued to Schlom et al.]. Similarly, monoclonal antibody KC-4 recognizes an approximately 400-500 kd protein antigen expressed on a number of carcinomas, such as colon, prostate, lung, and breast carcinoma [see U.S. Pat. No. 4,708,930]. It appears that neither the B72.3 nor KC-4 antibodies internalize within the carcinoma cells with which they react.
Monoclonal antibodies reactive with glycolipid antigens that are believed to be associated with certain tumor cells have also been disclosed. For example, W. W. Young et al., "Production of Monoclonal Antibodies Specific for Two Distinct Steric Portions of the Glycolipid Ganglio-N-Triosylceramide (Asialo GM.sub.2) ", J. Exp. Med., 150, pp. 1008-1019 (1979) disclose the production of two monoclonal antibodies specific for asialo GMhd, a cell surface glycosphingolipid antigen that was established as a marker for BALB/c3T3 cells transformed by Kirsten murine sarcoma virus. See, also, B. Kniep et al., "Gangliotriaosylceramide (Asialo GM.sub.2), A Glycosphingolipid Marker for Cell Lines Derived from Patients with Hodgkin's Disease", J. Immunol., 131 (No. 3) , pp. 1591-1594 (1983), and U.S. Pat. No. 4,507,391 (monoclonal antibody to human melanoma).
In addition, monoclonal antibodies reactive with glycolipid antigens found on specific types of carcinoma cells include those described by S. T. Rosen et al., "Analysis of Human Small Cell Lung Cancer Differentiation Antigens Using a Panel of Rat Monoclonal Antibodies", Cancer Research, 44, pp. 2052-2061 (1984), (monoclonal antibodies to human small cell lung cancer), N. M. Varki et al., "Antigens Associated with a Human Lung Adenocarcinoma Defined by Monoclonal Antibodies", Cancer Research, 44, pp. 681-687 (1984), (monoclonal antibodies to human adenocarcinomas of the lung, stomach and colon, and melanoma), and U.S. Pat. No. 4,579,827 (monoclonal antibodies to human colon adenocarcinoma). See, also, I. Hellstrom et al., "Antitumor Effects of L6, An IgG2a Antibody that Reacts with Most Human Carcinomas", Proc. Natl Acad. Sci. USA, 83, pp. 7059-7063 (1986) which describes the L6 monoclonal antibody that recognizes a carbohydrate antigen expressed on the surface of human non-small cell lung carcinomas, breast carcinomas, and colon carcinomas. The antigen with which the L6 antibody reacts is one that does not internalize within the carcinoma cell.
Other monoclonal antibodies exhibiting a reactivity to carcinoma cells are greatly needed. This is so because of the antigenic heterogeneity of many carcinoma tumors which often necessitates, in diagnosis or therapy, the use of a number of different monoclonal antibodies to the same tumor mass. Furthermore, monoclonal antibodies that display a high degree of selectivity to a wide range of carcinoma tissues are not common, and any such antibody would clearly be advantageous.
Of particular interest, especially in the area of therapeutic applications for monoclonal antibodies, would be so called "internalizing" antibodies, i.e., antibodies that are capable of being internalized within the tumor cell to which they bind. This type of antibody finds use in tumor therapy methods involving antibody-drug or antibody-toxin conjugates wherein a therapeutic antitumor agent is linked to an antibody for delivery to the site of a tumor, where the antibody binds to the tumor-associated antigen with which it is reactive and "delivers" the antitumor agent to the tumor site [see, e.g., M. J. Embleton et al., "Antibody Targeting of Anti-Cancer Agents", in Monoclonal Antibodies for Cancer Detection and Therapy, pp. 317-344 (Academic Press 1985)]. Because many antibodies to tumor-associated antigens are not able to internalize within the tumor cell to which they bind, often the antitumor agent is not able to reach its site of action within the cell. The use of an internalizing antibody as a component of the conjugate is believed to promote the antitumor activity of such a conjugate.
An example of an internalizing antibody is the anti-transferrin receptor antibody disclosed in D. L. Domingo et al., "Transferrin Receptor as a Target for Antibody-Drug Conjugates", Methods Enzymol., 112, pp. 238-247 (1985). This antibody is reactive with the human transferrin-receptor glycoprotein expressed on tumor cells. However, because the transferrin-receptor glycoprotein is also expressed on normal tissues, the use of an anti-transferrin-receptor antibody in a antibody-drug or antibody-toxin conjugate may have significant toxic effects on normal cells. The utility of this antibody for selective killing or inhibition of tumor cells is therefore questionable.
It is thus apparent that an antibody reactive with a carcinoma-associated antigen that is capable of being readily internalized by tumor cells and also displays a high degree of selectivity to a range of carcinoma cell types would be of great benefit in tumor therapy.